PRAGMATIC CONSIDERATIONS • Ethics of studies in children – FDA, EMA, other national ethics boards – ‘prevent harm to children’ – Risk/benefit: MDR, XDR, IPT – Ethics of not doing research in children • Implementation of trials in children – Timing in relation to adult trials – Recruitment, sampling for drug assay, adverse effect monitoring and data interpretation – End points: infection, death, TB disease - age specific: neonates to adolescents • Where are children with TB? – NICU, general paediatric services, hospitals to NTP • Formulations
Area Gaps for children Priority studies DS-TB • PK/safety first-line drugs at higher PK studies first-line drugs at doses, esp. infants, HIV+ higher dose: DAtiC, NICHD • Optimal treatment for TB meningitis PK/efficacy study in children: TBM-KIDS, NICHD • Treatment shortening DS-TB SHINE (nested PK) • FDC of FLD (2015) 36
Area Gaps for children Priority studies Co-treatment • Super boosting LPV/r in young children Super-boosted PI with HRZE (DnDI) TB/HIV taking HRZE EFV+HRZE in slow CYP2B6 genotype • EFV-based regimen in children < 3 years RAL or DTG-based ART with TB • INSTI-based ART with standard TB drugs drugs (PENTA, IMPAACT P1101) (HRZE) 37
Parallel group, non-inferiority trial • • 4 vs. 6 months, open label • Children aged 0-16 years • Non-severe TB • WHO-recommended doses first-line drugs N=1200 children • New FDC; 75, 50, 150 •
ROLE OF INDIVIDUAL DRUGS INH: Early bactericidal activity, rapid reduction in organism burden Rifampicin: Unique sterilizing activity against “ persisters ”, key contributor to cure without relapse Pyrazinamide: Sterilizing activity in acidic environments over the first 2 months, allowing for shortening of treatment Ethambutol: Prevents resistance to other antibiotics
Developmental pharmacology: A Moving Target Kearns, NEJM 2003 349: 1157. 40
WHO/IUATLD dosing guidelines for children <12 years of age Rifampicin (R): 15 (10-20) mg/kg 50% Isoniazid (H): 10 (7-15) mg/kg 100% Pyrazinamide: 35 (Z) (30-40) mg/kg 40% Evidence needed to support MINIMUM requirement - drug formulations and doses that achieve comparable PK to adults WHO/HTM/TB/2014.03; Burman et al. PLoS Med. 2008
Characteristics: n= 47 children n median IQR range Age (years) 47 2.9 (1.4, 6.4) 0.2, 10.1 Weight (kg) 47 13.4 (10.1, 18.4) Girls 18/47 (38%) HIV-infected 3/47 (6%) WFH -score 41 0 (0, 1) C-reactive protein (mg/L) 46 1.85 (1, 6.5) Albumin (g/L) 46 40 (38, 42) Rifampicin dose (mg/kg) 47 15.8 (13.4, 17.8) Isoniazid dose (mg/kg) 47 12.0 (11.1, 13.5) Pyrazinamide dose (mg/kg) 47 34.4 (32.1, 36.9) H McIlleron: NIH/NICHD R01HD069175 (DATiC study)
Isoniazid median for reference adult population weight (kg) <8 8-11.9 12-15.9 >16 n 5 13 14 15 median age (y) 1.3 2.6 7.1 1.1 (0.4,1.4) (range) (0.2,3.8) (1.5,5.4) (4.1,10.1) median dose (mg/kg) 13.9 13.5 11.4 11.2
Pharmacokinetics of Isoniazid in Low-Birth-Weight and Premature Infants Bekker et al. AAC 2014;58:2229 • LBW infants receiving 10 mg/kg of INH had desirable blood drug concentrations • Prolonged half-life and reduced elimination of INH noted in smaller and younger infants, especially in slow acetylators. • Caution against exceeding a dosage of 10 mg/kg here
Rifampicin AUC 0-24 8 children (17%) have median AUC > a reference adult population median AUC =28.3 mg.h/L weight (kg) <8 8-11.9 12-15.9 >16 n 5 13 14 15 median age (y) 1.3 2.6 7.1 1.1 (0.4,1.4) (range) (0.2,3.8) (1.5,5.4) (4.1,10.1) median dose (mg/kg) 11.3 15.8 15.4 14.5
MDR-TB TREATMENT
Area Gaps for children Priority studies DR-TB • PK/dosing second-line drugs (FQ, Modeling existing data, testing doses aminoglycosides, linezolid, clofazamine, PAS) predicted to achieve PK targets, optimal use, DDI • New drugs PK and safety (bedaquiline, PK/safety studies bedaquiline, PA- delamanid, PA-824, sutezolid) 824, DLM, BDQ and combinations • Injectable sparing shorter regimen Non-inferiority
MDR-TB TREATMENT OUTCOMES Outcome N = 149 (%) Cure 36 (24.2) Probable cure * 101 (67.8) Transferred out 1 (0.7) Lost to follow up 8 (5.4) Died 3 (2.0) Includes 8 patients who stopped their therapy before indicated but whoe were clinically well at follow up Seddon, Clin Infect Dis 2013
MDR-TB: ADVERSE EVENTS (n = 137) Grade of AE Gr 0 Gr 1 Gr 2 Gr 3-4 Any AE (%) Joint, muscle or bone pain 122 11 2 2 (1.5) 15 (10.9) Skin rashes 104 30 2 1 (0.7) 33 (24.1) Itchy skin 110 24 2 1 (0.7) 27 (19.7) Headache 120 16 1 0 17 (12.4) Sleep/mood problem 124 9 3 1 (0.7) 13 (9.5) Lethargy 118 17 1 1 (0.7) 19 (13.9) Visual problem 132 5 0 0 5 (3.6) Vomiting 113 20 3 1 (0.7) 24 (17.5) 125 10 1 1 (0.7) 12 (8.8) Diarrhoea Jaundice 133 1 2 1 (0.7) 4 (2.9) ↓ Appetite/nausea 118 14 3 1 (0.7) 18 (13.1) Hearing loss (n=142) 25 (17.6) Thyroxine supplementation (n=142; ↑ TSH 32 (22.5) & ↓ fT4) Seddon, Clin Infect Dis 2013
LEVOFLOXACIN IN CHILDREN 15 mg/kg daily Parameter Median (IQR) PK value (n=23) 6.71 C max (μg/ml) (4.69 - 8.06) AUC 0-8 29.89 (23.81 - 36.39) (μg∙h/ml) Parameter Mean (sd) PK Mean (sd) PK value/MIC value/MIC Target value if MIC is 0.5 if MIC is 1.0 8-10 13.1 (4.0) 6.5 (2.0) C max /MIC 100 65.3 (18.4) 32.6 (9.2) AUC/MIC No QTc prolongation, no significant clinical AE Thee, Antimicrob Agents Chemother, 2013
MOXIFLOXACIN PK IN CHILDREN 7-15 years (n=23) Mean AUC 0-24 /MIC: 56.1 Target: 100 Thee, Clin Infect Dis 2015 Mean Cmax/MIC: 6.5: Target: 8-10 Sirgel et al. JAC 2012 MIC 90 = 0.5 mg/L
NOVEL MDR-TB REGIMENS • Given good outcome, lower bacillary load, toxicities: injectable sparing shorter regimen • Optimizing role of safe and effective SLD: FQN, clofazamine, PAS, linezolid • Adult PK targets? PK/PD • Inclusion of novel drugs: DMD, BDQ • DDI data needed (also ARVs) • 9 months • Non-inferiority?
FDA approved 2012 EMA approved 2014
BEDAQUILINE PAEDIATRIC EVALUATION : P1108 • Delayed • Paediatric PK and safety studies (no efficacy) • Inclusion HIV-infected children: DDI • PK targets adults? • Risk/benefit • Long-term safety • Long half life, tissue bound • Confirmed and probable MDR-TB targeted • Need for age de-escalation? • Adaptive design, real-time PK assaying and modeling, dose adjustments • Formulation issues
EMA APPROVED 2014
DELAMANID • Trial 232: Phase 1 PK Age De-escalation study – Define dose of delamanid in children resulting in AUC comparable to the effective AUC observed in adult MDR-TB trials • Trial 233: Phase 2 Safety Study – Investigate the safety, tolerability, and PK of delamanid administered for six months in a pediatric population receiving concomitant OBR – Enrolling: Phillipines, South Africa; age de-escalation, HIV- IMPAACT P2005 in development : Delamanid PK and safety in HIV-co-infected children with MDR-TB : DDI
LTBI • Safety/tolerability/PK once-weekly INH/RPT • RPT dose for children under 2 for regimen for youngest children, DDI with ART weekly INH/RPT: Study 35 , child- friendly formulation • MDR LTBI • Efficacy and safety of long-term use of fluoroquinolones, novel drugs: Phoenix, TB-CHAMP, V-QUIN
No WHO-recommended regimen given absence of trial data: MDR- TB prevention regimen
Timeline for New First-Line Pediatric Formulations: Q2 2015: Dosage guidelines for children Q4 2014: <5kg Countries quantify cases of child TB Q1 2014: Initiate discussions with Q2/3 2015: First-line FDC GDF, Global Fund, products available to other donors Q1 2015: Manufacturers Q2 2016: All first-line procure through GDF submit for WHO PQ and products WHO pre- and/or Importation local registration qualified and available waivers 2013: in the market Q2 2014:Three Project manufacturing partners Launch secured
SUMMARY • Significant research gaps in DS-TB, DR-TB • Special populations: LBW, adolescents, HIV c-infected • Multiple interventional trials planned or ongoing • Need for earlier inclusion of children in evaluating novel drugs and regimens • Significant gains made • Need for child-friendly approaches
ACKNOWLEDGEMENTS Simon Schaaf Tony Garcia-Prats Steffi Thee Peter Donald Heather Draper Helen McIlleron Jennifer Norman Lubbe Wiesner Peter Smith Marianne Willemse Sharon Nachman James Seddon Kelly Dooley Rada Savic M)— Elin Svensson Mats Karlson Study participants and their parents/care-givers! – ®
Tuberculosis in Pregnancy Amita Gupta MD MHS Associate Professor of Medicine and International Health Johns Hopkins University HANC Webinar May 27, 2015
Disclosures • Amita Gupta has no financial relationships with commercial entities to disclose • Amita Gupta receives research grant funding from the – US NIH (NIAID, NICHD, Fogarty, CFAR) – US CDC – Indian Department of Biotechnology and Indian Council of Medical Research – Foundations (Gilead, Wyncote, Ujala) • Any opinions expressed are my own and not of any of my sponsors.
Overview • Global TB burden and epidemiology • Impact on maternal-child health outcomes • Screening for active and latent TB infection (LTBI) in pregnancy/ postpartum • Treatment
What is the burden of TB in pregnancy?
TUBERCULOSIS IN WOMEN • 2014 – >500,000,000 latently infected – 3.3 million with active TB (37% of global burden) – 510,000 died (180,000 HIV-infected) – 50% of HIV-related TB deaths – 67% of cases Africa and SE Asia – More than 50% of female TB cases went undetected – >216,000 cases in pregnancy estimated WHO Global TB Report 2014 Sugarman, Lancet Global Health 2014
Peak TB incidence in women of reproductive age irrespective of HIV Sub-Saharan African Women Deluca JAIDS 2009 TB Cases per 100,000 Indian women TB Cases per 100,000 RNTCP: Gender differentials in TB control 2004 Age, years
Prevalence of TB in pregnancy • No national reporting for high burden countries • Data based on individual screening studies Active TB Study Site HIV-negative HIV-positive Low burden countries 0.06-0.25% 1% High-burden countries 0.07-0.53% 0.69-11% Latent TB Study Site HIV-negative HIV-positive Low burden countries 10-23% 11-26% High-burden countries 18-34% 21-49% Mathad & Gupta, CID 2012
Prevalence of TB disease in HIV-infected pregnant women in high burden settings Study Year Country N Prevalence (95% CI) Pillay 2001 S. Africa 14650 0.8 (0.6, 0.9) Kalli 2006 S. Africa 370 2.2 (0.9, 4.2) TiPs* 2014 Kenya 288 2.4 ( 0.1, 4.2) Hoffman* 2013 S. Africa 1415 2.5 (1.7, 3.4) Jonnalagadda 2010 Kenya 393 2.8 (1.4, 4.9) Gupta 2007 India 715 3.4 (2.2, 4.9) Modi* (unpub) 2014 Kenya 134 6.0 (2.6, 11.4) Gounder 2011 S. Africa 1427 0.6 (0.4, 0.7) Leroy 1995 Rwanda 211 7.9 (4.8, 12.6) Sheriff 2010 Tanzania 396 10.0 (1.2, 31.7) Nachega 2003 S. Africa 120 11.0 (5.9, 17.8) 0 5 10 15 20 *culture obtained independent of symptoms Prevalence: 0.6-11% Slide courtesy of Sylvia LaCourse, Univ of Washington
Impact of Maternal TB on maternal-infant outcomes?
Risk of complications in pregnancy TB vs. no TB Maternal complications • Pre-eclampsia & eclampsia (2 fold) • Vaginal bleeding (2 fold) • Hospitalization (12 fold) • Miscarriage (10 fold) Bothalmley 2001 Jana Int J Gyn Obstet 1994 Pillay Lancet ID 2000; Jana NEJM 1999 Mathad CID 2012 Chin HC BJOG 2010 Bjerkedal 1975
Risk of complications in pregnancy TB vs. no TB Fetal and infant complications • Fetal death (increased) • Low birth weight (2 fold) • Lower Apgar scores • Prematurity (2 fold) • Small for gestational age (2 fold) • Perinatal death (increased) • congenital TB (rare) • Increased HIV transmission (2 fold) Jana Int J Gyn Obstet 1994 Khan AIDS 2001; Jana NEJM 1999 Pillay Lancet ID 2000; Chin HC BJOG 2010 Gupta JID 2011
Postpartum TB important causes maternal and infant mortality in HIV infected women HIV-infected mothers have 10-fold increase in TB. Maternal TB/HIV increased risk of postpartum mortality by 2.2 fold and probability of infant death by 3.4 fold . Materal TB No Maternal TB 715 HIV-infected Mortality Incidence, 8.5 pregnant women in 10 Pune, India #/100/pt-yr Infant death Maternal death aIRR = 3.4 8 aIRR 2.2 p=0.02 p=0.006 TB incidence 5/100 pt-yr (24 of 715 HIV+ women) 6 2.5 4 0.9 0.4 2 0 Mother Infant Gupta A et al. Clin Infect Dis 2007;45:241-9
Does pregnancy or the postpartum period increase the risk of TB acquisition? reactivation? severity?
Pregnancy-associated immune changes are biologically significant • Systemic immunomodulation that simultaneously embraces cellular immunosuppression, immunotolerance to various antigens, and enhanced inflammatory response. Improved course of multiple sclerosis and rheumatic arthritis Aggravated systemic lupus erythematosus risk of plasmodium falciparum malaria, listeriosis, HIV severity of influenza, hepatitis E, HSV, malaria, measles, smallpox, varicella, coccidiomycosis Adapted from Kourtis NEJM 2014 Confavreux N Engl J Med 1998;Gordon Best Pract Res Clin Rheumatol 2004;Lindsay. Am J Epidemiol 2006; Diagne. Trans R Soc Trop Med Hyg 1997;Kumar. J Reprod Med 1997; Kourtis NEJM 2014
Risk of TB in Pregnancy: UK primary care cohort Impact on TB reactivation and severity debated Clinical data limited and were not consistent or convincing ( Good Am. J. Obstet. Gynecol 1981, Carter Chest 1994, Espinal 1996;Sterling 2007) • 192,801 women enrolled 1996-2008 IRR 1.95 • with 264,136 pregnancies Postpartum TB • Mean f/up 9.1 years, 1,745,834 PY • 177 TB events; postpartum • 15.4 vs 9.1/100,000 PY Zenner AJRCCM 2011
Does pregnancy impact performance of screening for active or latent TB?
TB diagnostic sensitivity of WHO 4-symptom screen in pregnancy 90% WHO Sx screen 80% 79% 80% Smear 70% Xpert 60% 54% Urine LAM 50% 50% 43% 43% 40% 34% 28% 30% 20% 10% 1.40% 0 0% 0 0 0 0% Hoffman LaCourse Gupta PLWHIV At least one WHO 4-symptom in 9-19% of women Compared to non-pregnant HIV infected adults • Lower sensitivity observed but not clear if that is due to pregnancy alone • High negative predictive value (NPV) BUT • High prevalence of undiagnosed asymptomatic TB (HoffmanPLOS One 2013, #822) TIPS data courtesy of LaCourse and Cranmer, UW
Current recommendations LTBI screening Low-burden countries 1 : High-burden countries: • TST or IGRA for “high risk” • WHO does not recommend – TB contacts routine LTBI screening – HIV – Exceptions: – Anti-TNF treatment • HIV+ 3 , – Dialysis, silicosis, or transplant • TB contacts < 5yo 4 patients – IGRA not recommended 5 – Foreign birth, IVDA, congregate settings 2 1 WHO LTBI Guidelines 2015; 2 CDC 2013; 3 WHO Intensified Case finding 2011 4 WHO Contact tracing Recs 2012 5 WHO IGRA Policy 2011
Screen for latent TB? • Goal of Latent TB screening – Identify those at highest risk for reactivation disease – Target preventive therapy • Implementation challenges • Little attention paid to performance of latent TB diagnostics in pregnant/postpartum women in era of HIV • Mixed data – Two US studies of IGRA (Quantiferon) test positivity was lower than TST (older age, foreign birth associated with positivity) (Worjohol et al Obstet Gynecol 2011; Chebab Kansas J Med 2010) – India, more Quantiferon positive than TST and discordance QGIT+/TST- was higher (Mathad, PLOS One 2014) • Positive IGRA predictive of active TB postpartum ( Jonalagadda JID 2010, IJTLD 2013
TST vs IGRA positivity rates: When women screened and which latent TB diagnostic test used matters 52% N=450 HIV-negative women in India 31% 32% 25% 17% 10% Mathad et al PLOS One 2014
Does pregnancy impact TB treatment and prevention?
Physiology Changes of Pregnancy Can Significantly Impact Drug Metabolism, Safety and Efficacy Increased cardiac Decreased lung • Increased body fat output capacity • Increased total body weight Decreased gastric • Decreased albumin emptying Changes in hepatic • Hepatic metabolism metabolism Decreased stomach – Increased CYP3A4 pH – Decreased CYP1A2 and Increased GFR CYP2C19 Frederiksen, Sem Perinatol 2001; Anderson, Clin Pharmacokinetics 2005
Importance of studying TB/HIV drugs in pregnancy: INH and EFV example The population PK model post-hoc estimates were used to predict individual C min Pre/intrapartum 6 weeks Post-partum (n=73) (n=75) C min (mg/L)* 1.35 (0.90-2.07) 2.00 (1.40-3.59) % with C min <1 mg/L 27% 13% • Pregnancy modestly reduces EFV exposures, even after adjusting for weight, and proportion of women with EFV Cmin<1 mcg/mL higher in pregnancy than postpartum – especially in extensive CYP2B6 metabolizers • TB treatment that includes INH and RIF doesn’t reduce EFV concentrations, but EFV exposures higher in patients with slow NAT2 genotype taking INH • No increased HIV MTCT noted *Median (IQR) Dooley et al., JID 2014 TSHIEPO study
Drug-Drug Interactions HIV/TB and contraception • Rifamycins and antiretrovirals – IMPAACT P1026s first line TB drugs with and without ARVs (EFV, LPV/r, NVP) now underway – Need data for • Protease inhibitors and rifabutin • Raltegravir and rifampin • Rifamycins and hormonal contraceptives – Rifampin reduces OCP mean AUC but did not reverse suppression of ovulation (Barditch-Crovo Clin Pharm & Therap 1999) – Interaction with Depo-Provera, Implanon, ARVs? (ACTG 5338)
www.fda.gov
First line drugs for TB in pregnancy Drug FDA Crosses Breast- Issues in pregnant women placenta feeding INH C Yes Yes Hepatotoxicity Rifampin C Yes Yes Drug interactions with NVP, PIs, OCPs; may require Vit K Rifabutin B Unk Unk Drug interactions with PIs, limited experience EMB B Yes Yes PZA C Unk Unk Different guidance Brost Obstet Gyn Clin 1997;Bothamley Drug Safety 2001;Shin CID 2003; Micromedex; Mathad & Gupta CID 2012
Treatment of Active Pulmonary TB in Pregnancy Low Burden 1 High Burden 2 HIV negative INH 5mg/kg/d x 9 mo INH 5 mg/kg/d × 6 mo RIF 10mg/kg/d x 9mo RIF 10 mg/kg/d × 6 mo EMB wt-based x 2 mo EMB 15mg/kg/d x 2 mo B6 25mg/d x 9 mo PZA 25mg/kg/d x 2 mo B6 10-25mg/d x 6 mo HIV positive INH 300 mg/d × 6 mo INH 5 mg/kg/d × 6 mo RIF 600 mg/d × 6 mo RIF 10 mg/kg/d × 6 mo EMB wt-based x 2mo EMB 15mg/kg/d x 2 mo PZA wt-based × 2 mo PZA 25mg/kg/d x 2 mo B6 25mg/d x 6 mo B6 10-25mg/d x 6 mo LACTATION CDC encourages breastfeeding if no longer infectious; WHO once smear negative DIFFERENCE IN PZA guidance 1 CDC, ATS, IDSA guidelines 2 WHO, British thoracic Society, RNTCP and IUATLD guidelines Treatment of EPTB involves same drugs but most experts recommend 9-12 mo for TBM (but include PZA plus steroids) or bone/joint infections
Drug-resistant TB in pregnancy? Drug FDA Category Aminoglycosides D Capreomycin C Fluoroquinolones C Ethionamide/Prothionamide C Cycloserine C PAS C Linezolid C Clofazamine C Bedaquiline B Delaminid EMA approved no teratogenicity but use with great caution
MDR TB in pregnancy • Treatment guidelines similar to non-pregnant adults – Individualized treatment vs public health approach – At least 4 new agents – Favor injectable after delivery – Lactation little to no data so often not recommended • >57 published case reports (Gach 1999;Shin 2003; Nitta 1999;Lessnau 2003;Tabarsi 2007; Khan 2007; Palacios 2009; Toro 2011) – 3 case series describes 4 cases HIV+ (Khan 2007; Palacios 2009, Toro 2011) – US, Italy, Peru, Iran, South Africa • Regimens: variable • Outcomes: case series suggest treatment success possible
Treatment as Prevention: The Case for Latent TB Treatment in Pregnancy
Guidelines for Preventive TB Treatment in Pregnant Women Low Burden (US CDC) High Burden (WHO) Regimen INH 300mg/d x 9 mo INH 300mg/d x 6 or 36 mo B6 25-50mg/d x 9 mo B6 10-25mg/d x 6 or 36 mo OR INH 900mg twice weekly x 9 mo B6 25-50mg/d x 9 mo HIV-negative Defer for TST+ or IGRA+ until 2-3 mo No recommendations postpartum unless known recent TB contact HIV-positive Immediate treatment for TST+ or IGRA+ Treatment for all HIV+ without active TB
>40 trials listed here that are planned, ongoing or recently completed At least 8 are Phase III trials All exclude pregnant women More than 13 trials of preventive therapy in HIV-infected adults INH for 6, 9, 12, 36 months INH+ rifampin INH+ rifapentine INH+ ART All excluded pregnant women Akolo Cochrane metanalysis 2010; Sterling NEJM 2011; Martinson NEJM 2011; Samandari Lancet 2011; Rangaka Lancet ID 2014
Some TB trials and studies underway in pregnant women! Treatment Prevention • IMPAACT P1078 • IMPAACT P1026s – TB APPRISE: Phase IV double blind RCT of – PK/Safety of 1 st line TB drugs with or antepartum vs postpartum INH for HIV+ without ARVs pregnant women in high TB burden • THSIEHPO (NICHD- Chaisson) settings – PK/safety of EFV/RIF, EFV/INH • IMPAACT P2001 – PK/safety of INH/rifapentine weekly for 12 weeks in HIV+ and HIV- • ACTG/IMPAACT PHOENIX MDR contact prophylaxis
Filling the gaps for maternal TB Epidemiology of latent and active TB Implementation Science -PMTCT/TB screening &IPT NICHD TSHIEPO MOHs Lesotho, Kenya, South Africa TIPS, India, Haiti studies, CDC, USAID, JHPIEGO, ICAP IMPAACT PROMISE ARVs /ATT drug interactions Immunology and pathogenesis of TB A5388 (PK ARV, Rifampin, contraception) NICHD TSHIEPO IMPAACT P1078 NICHD Pregnancy Immune Changes/TB PK, safety, and outcome studies of: -LTBI regimens -1 st and 2 nd line TB medications Cost-effectiveness studies for TB IMPAACT Pregnancy studies screening/treatment P1078 (RCT of antepartum vs postpartum INH) P2001 (PK, safety INH/rifapentine weekly) P1026s (PK 1 st line TB drugs and ARVs) A5300/P2003 PHOENIX MDR contact
Summary • Peak incidence of TB during reproductive age • Maternal TB associated with adverse pregnancy outcomes, maternal mortality and infant TB and mortality • Immune and physiological changes may be of importance to screening diagnostic yield, TB drug disposition • Best approaches of integrated TB screening and prevention needed • Need to include pregnant women in trials of diagnostics and drugs whenever feasible • Several studies now ongoing that will help to fill in the knowledge gap
Acknowledgements JHU-CCGHE-BJMC India NIRT/ICER Bob Bollinger Soumya Swaminathan Jyoti Mathad (Cornell) Subhash Babu Vidya Mave UW Nikhil Gupte Sylvia Lacourse Rupak Shivakoti Lisa Cramner Akshay Gupte Grace John Stewart Natasha Chida Nishi Suryavanshi U. Colorado Jane McEnzie-White Adriana Weinberg Ramesh Bhosale Stellenbosch Renu Bharadwaj Anneke Hesseling Ajay Chandanwale Gerhard Theron Sameer Joshi Aarti Kinikar WHO Sandesh Patil Haileyesus Getahun Charles Flexner NIAID R01AI080417, UM1AI069465, R01A1I097494 ACTG and IMPAACT JHU Center for TB Research NICHD R01HD081929, R01HD074944 investigators Richard Chaisson Fogarty D43TW000010, CFAR 1P30AI094189 Kelly Dooley Foundations: Ujala, Wyncote, Gilead Women and children Jonathan Golub participants
COMMUNITY ENGAGEMENT — AND COLLABORATION — IN TB/HIV RESEARCH Lindsay McKenna, MPH Project Officer, TB/HIV Treatment Action Group May 27, 2015
Who We Are & Where We Are Going • About the Community Research Advisors Group (CRAG) and the Tuberculosis Trials Consortium (TBTC) • About Community Partners (CP) and the National Institutes of Health (NIH) HIV/AIDS clinical trials networks • About TB and TB/HIV research • Why CRAG and CP are working together • The issues in TB/HIV research we’re thinking about
About the CRAG • an international, community-based advisory body; • ensures the meaningful engagement of TB-affected communities in research conducted by the TBTC; • supports a TBTC research agenda that is responsive to community needs and scientific priorities. 8 members from TBTC sites in 6 countries: • United States; • South Africa; • Uganda; • Vietnam; • Spain; • Peru
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